Certain aryl and cycloalkyl fused imidazopyrazinediones; a new class of GABA brain receptor ligands

ABSTRACT

The present invention encompasses compounds of the formula: ##STR1## and the pharmaceutically acceptable non-toxic salts thereof wherein: where X represents hydrogen of lower alkyl; 
     W represents an aryl group unsubstituted or substituted with various organic and inorganic substitutents; ##STR2## where A, B, C, D, and E represent carbon or nitrogen substituted with hydrogen or various organic and inorganic substituents; and 
     n is 0, 1, or 2, Y, R 3 , R 4 , R 12 , and R 13  are various organic and inorganic substituents. 
     These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs thereof and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs, and enhancement of memory.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain aryl and cycloalkyl fusedimidazopyrazinediones which selectively bind to GABAa receptors. Thisinvention also relates to pharmaceutical compositions comprising suchcompounds. It further relates to the use of such compounds in treatinganxiety, sleep and seizure disorders, and overdoses ofbenzodiazepine-type drugs, and enhancing alertness. The interaction ofaryl and cycloalkyl fused imidazopyrazinediones of the invention with aGABA binding site, the benzodiazepines (BDZ) receptor, is described.This interaction results in the pharmacological activities of thesecompounds.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 30 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. In most regions of the brain, GABA isassociated with local inhibitory neurons and only in two regions is GABAassociated with longer projections. GABA mediates many of its actionsthrough a complex of proteins localized both on cell bodies and nerveendings; these are called GABAa receptors. Postsynaptic responses toGABA are mediated through alterations in chloride conductance thatgenerally, although not invariably, lead to hyperpolarization of thecell. Recent investigations have indicated that the complex of proteinsassociated with postsynaptic GABA responses is a major site of actionfor a number of structurally unrelated compounds capable of modifyingpostsynaptic responses to GABA. Depending on the mode of interaction,these compounds are capable of producing a spectrum of activities(either sedative, anxiolytic, and anticonvulsant, or wakefulness,seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazepam, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs; such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207: 274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the "receptor" for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &Pkada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 mM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepam-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. The data were interpreted to means that both GABA andbenzodiazepine sites were allosterically linked in the membrane as partof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor antagonist (+) bicuculline; thestereoisomer (-) bicuculline is much less active (Tallman et al., 1978,Nature, 274: 383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity or negativecooperativity. In these studies, Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, triazolopyridazine interactedwith benzodiazepine sites with a Hill coefficient of 1 (Squires et al.,1979, Pharma. Biochem. Behav. 10: 825-30, Klepner et al. 1979,Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepinereceptors were predicted in the cortex, hippocampus, striatum, but notin the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have molecular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent "isoreceptors" or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The g subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds; agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine(Hunkeler et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards, 1981, Nature 294: 763-65), itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous.

A biochemical test for the pharmacological and behavioral properties ofcompounds that interact with the benzodiazepine receptor continues toemphasize the interaction with the GABAergic system. In contrast to thebenzodiazepines, which show an increase in their affinity due to GABA(Tallman et al., 1978, Nature 274: 383-85, Tallman et al., 1980, Science207: 274-81), compounds with antagonist properties show little GABAshift (i.e., change in receptor affinity due to GABA) (Mohler & Richards1981, Nature 294: 763-65), and the inverse agonists actually show adecrease in affinity due to GABA (Braestrup & Nielson 1981, Nature 294:472-474). Thus, the GABA shift predicts generally the expectedbehavioral properties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. For example, U.S. Pat. Nos. 4,312,870 and 4,713,383, andEuropean Patent Application EP 181,282 disclose assorted compoundsuseful in treating anxiety or depression. U.S. Pat. No. 4,713,383teaches compounds of the formula: ##STR3## wherein R₁ =(un)substitutedPh, (dihydro)furanyl, tetrahydrofuranyl, (dihydro)thienyl,tetrahydrothienyl, pyranyl, ribofuranosyl, all C-attached; R₂ =H, alkyl;X=O, S, R₃ N; R₃ =H, alkenyl, alkynyl, C₃₋₂₀ cycloalkyl, (un)substitutedalkyl, aryl, aralkyl, where aryl is Ph, pyridinyl, thienyl, furanyl;ring A may be substituted by alkyl, alkoxy, halo, amino, alkylthio, etc.

European Patent Application EP 181,282 discloses compounds of theformula: ##STR4## wherein R₁ =(substituted) Ph or heterocycle; R₂ =H,alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl, aryl; R₃ =H, alkyl,alkoxy, HO, halo, F₃ C, O₃ N, H₂ N, alkylthio, alkylsulfinyl,alkylsulfonyl, aralkoxy; X=O, S, NR₄ ; and R₄ =H, alkyl, aralkyl,cycloalkyl, alkenyl, alkynyl, aryl, (substituted) aminoaklyl,hydroxyalkyl.

U.S. Pat. No. 4,312,870 teaches compounds of formulas: ##STR5## where Phis 1,2-phenylene, unsubstituted or substituted by up to 3 identical ordifferent members selected from lower alkyk, lower alkoxy, loweralkylthio, hydroxy, halogeno, trifluoromethyl, nitro, amino, mono- ordi-lower alkylamino, cyano, carbamoyl and carboxy; R is unsubstituted orsubstituted phenyl as defined by H-Ph, pyridyl, lower alkylpyridyl, orhalogenopyridyl; R₁ is hydrogen, lower alkyl or lower (hydroxy,dialkylamino or H-Ph)-alkyl; and R₂ is hydrogen or lower alkyl alkyl;their 3-hydroxytautomers; lower alkanoyl, carbamoyl, mono- or di-loweralkylcarbamoyl derivatives of said (hydroxy or amino)-(phenyl orphenylene) compounds:

and ##STR6## where R" is hydrogen, alkyl or alkoxy with up to 4 carbonatoms each, hydroxy, fluoro, chloro, bromo, or trifluoromethyl; and R'is hydrogen, o- or m-fluoro; or it is p-fluoro when R" is chloro.

The compounds of the present invention differ from these compounds.These compounds are not imidazopyrazines and lack the various ringsubstituents of the compounds of the present invention.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in enhancingalertness, treatment of seizure, anxiety, and sleep disorders, andtreatment of benzodiazepine overdoses. Accordingly, a broad embodimentof the invention is directed to compounds of Formula I: ##STR7## and thepharmaceutically acceptable non-toxic salts thereof wherein: X ishydrogen or lower alkyl having 1-6 carbon atoms;

W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; ##STR8## wherein: Arepresents nitrogen or C--R₁ ;

B represents nitrogen or C--R₂ with the proviso that not both A and Bare nitrogen;

C represents nitrogen or C--R₁ ;

D represents nitrogen or C--R₂ with the proviso that not both C and Dare nitrogen;

E represents oxygen, sulfur or N--R₅ ;

R₁ and R₄ are the same or different and represent hydrogen, halogen,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms; and

R₃ and R₅ are the same or different and represent hydrogen or straightor branched chain lower alkyl having 1-6 carbon atoms; or ##STR9## wheren is 0, 1 or 2;

R₁₂ and R₁₃ are the same or different and represent hydrogen or straightchain or branched lower alkyl having 1-6 carbon atoms;

Y is

N--R₁₄ where R₁₄ is

hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms;

aminoalkyl where the alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkylis a straight or branched chain lower alkyl having 1-6 carbon atoms;

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl) eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

--COR₁₅ or --SO₂ R₁₅ where R₁₅ is straight or branched chain lower alkylhaving 1-6 carbon atoms, phenyl, pyridyl, phenylalkyl or pyridylalkylwhere each alkyl is straight or branched chain lower alkyl having 1-6carbon atoms, or phenylalkoxy or pyridylalkoxy where each alkoxy isstraight or branched chain lower alkoxy having 1-6 carbon atoms;

--CO--, --CR₁₇ OR₁₆, --CR₁₇ COR₁₆, --CR₁₇ CO₂ R₁₆, --CR₁₇ OCOR₁₆, and--CR₁₆ R₁₇, where

R₁₆ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms, andR₁₇ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms;

--CR₁₇ CONR₁₈ R₁₉ or --CR₁₇ (CH₂)_(n) NR₁₈ R₁₉ where

n is 0, 1, or 2, and

R₁₇ and R₁₈ are the same or different and represent hydrogen, straightor branched chain lower alkyl having 1-6 carbon atoms, and

R₁₉ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms, or

NR₁₈ R₁₉ together forms a heterocyclic group which is morpholyl,piperidyl, pyrrolidyl, or N-alkylpiperazyl;

--CR₁₇ NR₂₀ CO₂ R₂₁ where

R₁₇ is hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, and

R₂₀ and R₂₁ are the same or different and represent hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CR₁₇ C(OH)R₂₂ R₂₃ where

R₂₂ and R₂₃ are the same or different and represent straight or branchedchain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl, straight orbranched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms and

R₁₇ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms; ##STR10## where n is 0, 1, or 2,

R₂₄ is hydrogen, aryl, heteroaryl, straight or branched chain loweralkyl having 1-6 carbon atoms, or aryl or heteroaryl straight orbranched chain lower alkyl having 1-6 carbon atoms;

Z is methylene, oxygen, NR₂₅ or --CHCONR₂₅ where R₂₅ is hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,pyridyl, or phenylalkyl or pyridyl alkyl where each alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; and

T is methylene or oxygen.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs of agonists, antagonistsor inverse agonists for GABAa brain receptors. These compounds areuseful in the diagnosis and treatment of anxiety, sleep, and seizuredisorders, overdose with benzodiazepine drugs, and enhancement ofmemory.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-C show representative aryl and cycloalkyl fusedimidazopyrazinediones of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by the following general formula I: ##STR11## and thepharmaceutically acceptable non-toxic salts thereof wherein: X ishydrogen or lower alkyl having 1-6 carbon atoms;

W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; ##STR12## wherein:A represents nitrogen or C--R₁ ;

B represents nitrogen or C--R₂ with the proviso that not both A and Bare nitrogen;

C represents nitrogen or C--R₁ ;

D represents nitrogen or C--R₂ with the proviso that not both C and Dare nitrogen;

E represents oxygen, sulfur or N--R₅ ;

R₁ and R₄ are the same or different and represent hydrogen, halogen,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms; and

R₃ and R₅ are the same or different and represent hydrogen or straightor branched chain lower alkyl having 1-6 carbon atoms; or ##STR13##where n is 0, 1 or 2;

R₁₂ and R₁₃ are the same or different and represent hydrogen or straightchain or branched lower alkyl having 1-6 carbon atoms;

Y is

N--R₁₄ where R₁₄ is

hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms;

aminoalkyl where the alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkylis a straight or branched chain lower alkyl having 1-6 carbon atoms;

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl) eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

--COR₁₅ or --SO₂ R₁₅ where R₁₅ is straight or branched chain lower alkylhaving 1-6 carbon atoms, phenyl, pyridyl, phenylalkyl or pyridylalkylwhere each alkyl is straight or branched chain lower alkyl having 1-6carbon atoms, or phenylalkoxy or pyridylalkoxy where each alkoxy isstraight or branched chain lower alkoxy having 1-6 carbon atoms;

--CO--, --CR₁₇ OR₁₆, --CR₁₇ COR₁₆, --CR₁₇ CO₂ R₁₆, --CR₁₇ OCOR₁₆, and--CR₁₆ R₁₇, where

R₁₆ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms, and

R₁₇ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms;

--CR₁₇ CONR₁₈ R₁₉ or --CR₁₇ (CH₂)_(n) NR₁₈ R₁₉ where

n is 0, 1, or 2, and

R₁₇ and R₁₈ are the same or different and represent hydrogen, straightor branched chain lower alkyl having 1-6 carbon atoms, and

R₁₉ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms, or

NR₁₈ R₁₉ together forms a heterocyclic group which is morpholyl,piperidyl, pyrrolidyl, or N-alkylpiperazyl;

--CR₁₇ NR₂₀ CO₂ R₂₁ where

R₁₇ is hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, and

R₂₀ and R₂₁ are the same or different and represent hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CR₁₇ C(OH)R₂₂ R₂₃ where

R₂₂ and R₂₃ are the same or different and represent straight or branchedchain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl, straight orbranched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms and

R₁₇ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms; ##STR14## where n is 0, 1, or 2,

R₂₄ is hydrogen, aryl, heteroaryl, straight or branched chain loweralkyl having 1-6 carbon atoms, or aryl or heteroaryl straight orbranched chain lower alkyl having 1-6 carbon atoms;

Z is methylene, oxygen, NR₂₅ or --CHCONR₂₅ where R₂₅ is hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,pyridyl, or phenylalkyl or pyridyl alkyl where each alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; and

T is methylene or oxygen.

In addition, the present invention encompasses compounds of Formula II.##STR15## wherein: R₃ and X are the same or different and representhydrogen or straight or branched chain lower alkyl having 1-6 carbonatoms;

W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₄ is hydrogen, halogen, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl.

The present invention also encompasses compounds of Formula III:##STR16## wherein: W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₁ and R₄ are the same or different and represent hydrogen, halogen,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; and

R₃ and X are the same or different and represent hydrogen or straight orbranched chain lower alkyl having 1-6 carbon atoms.

The present invention also encompasses compounds of Formula IV:##STR17## wherein: W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

E represents oxygen, sulfur, N--H, or N--Me;

R₁ is hydrogen, halogen, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl;1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl; 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; and

X represents hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms.

The present invention also encompasses compounds of Formula V: ##STR18##wherein: W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

E represents oxygen, sulfur, N--H, or N--Me;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl;1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; and

R₄ and X are the same or different and represent hydrogen or straight orbranched chain lower alkyl having 1-6 carbon atoms.

The present invention also encompasses compounds of Formula VI:##STR19## wherein: W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

E represents oxygen, sulfur, N--H, or N--Me;

R₁ and R₄ are the same or different and represent hydrogen, halogen,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; and

X represents hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms.

The present invention also encompasses compounds of general formula VII:##STR20## wherein: n is 0, 1 or 2;

R₁₂ and R₁₃ are the same or different and represent hydrogen or straightor branched chain lower alkyl having 1-6 carbon atoms;

R₁₆ is hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, pyridyl, or phenylalkyl or pyridylalkyl where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;

W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight, or branched chain lower alkyl having1-6 carbon atoms, amino, mono or dialkylamino where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; and

X represents hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms.

The present invention also encompasses compounds of general formulaVIII: ##STR21## where R₁₂ and R₁₃ are the same or different andrepresent hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms;

W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₁₄ is

hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms;

aminoalkyl where the alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkylis a straight or branched chain lower alkyl having 1-6 carbon atoms;

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydro-naphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydro-naphthyl) eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

--COR₁₅ or --SO₂ R₁₅ where R₁₅ is straight or branched chain lower alkylhaving 1-6 carbon atoms, phenyl, pyridyl, phenylalkyl or pyridylalkylwhere each alkyl is straight or branched chain lower alkyl having 1-6carbon atoms, or phenylalkoxy or pyridylalkoxy where each alkoxy isstraight or branched chain lower alkoxy having 1-6 carbon atoms; and

X represents hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms.

The present invention also encompasses compounds of general formula IX:##STR22## where W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

Z is methylene, oxygen or NR₂₅ where R₂₅ is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

T is methylene or oxygen;

U is methylene or carbonyl; and

X represents hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. Iand their pharmaceutically acceptable salts. The present invention alsoencompasses the acylated prodrugs of the compounds of Formula I. Thoseskilled in the art will recognize various synthetic methodologies whichmay be employed to prepare non-toxic pharmaceutically acceptableaddition salts and acylated prodrugs of the compounds encompassed byFormula I.

By lower alkyl in the present invention is meant straight or branchedchain alkyl groups having 1-6 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By lower alkoxy in the present invention is meant straight or branchedchain alkoxy groups having 1-6 carbon atoms, such as, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,and 3-methylpentoxy.

By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

By N-alkylpiperazyl in the invention is meant radicals of the formula:##STR23## where R is a straight or branched chain lower alkyl as definedabove.

By 4-(thia)deoxachromanyl is meant a radical of the formula: ##STR24##

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3:433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20'. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at -20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure i carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand0.5 nM (³ H-RO15-1788 [³ H-Flumazenil] specific activity 80 Ci/mmol),drug or blocker and buffer to a total volume of 500 ml. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice andfresh 0.05M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total-Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to a form for thecalculation of IC₅₀ and Hill Coefficient (nH). Data for the compounds ofthis invention are listed in Table I.

                  TABLE I                                                         ______________________________________                                        Compound Number.sup.1                                                                          IC.sub.50 (uM)                                               ______________________________________                                        1                0.010                                                        5                0.009                                                        8                0.020                                                        ______________________________________                                         .sup.1 Compound numbers relate to compounds shown in FIG. I.             

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present inventionis given in Schemes I and II. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present invention, asdemonstrated by the following examples. ##STR25## wherein:

W is

phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₂ is

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thia)deoxachromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆ R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms;

R₃ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms;

R₄ is hydrogen, halogen, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; and

Y is

N--R₁₄ where R₁₄ is

hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms;

aminoalkyl where the alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkylis a straight or branched chain lower alkyl having 1-6 carbon atoms;

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydro-naphthyl) eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6 carbon, atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

--COR₁₅ or --SO₂ R₁₅ where R₁₅ is straight or branched chain lower alkylhaving 1-6 carbon atoms, phenyl, pyridyl, phenylalkyl or pyridylalkylwhere each alkyl is straight or branched chain lower alkyl having 1-6carbon atoms, or phenylalkoxy or pyridylalkoxy where each alkoxy isstraight or branched chain lower alkoxy having 1-6 carbon atoms;

--CO--, --CR₁₇ OR₁₆, --CR₁₇ COR₁₆, --CR₁₇ CO₂ R₁₆, --CR₁₇ OCOR₁₆, and--CR₁₆ R₁₇, where

R₁₆ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms, and

R₁₇ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms;

--CR₁₇ CONR₁₈ R₁₉ or --CR₁₇ (CH₂)_(n) NR₁₈ R₁₉ where

n is 0, 1, or 2, and

R₁₇ and R₁₈ are the same or different and represent hydrogen, straightor branched chain lower alkyl having 1-6 carbon atoms, and

R₁₉ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms, or

NR₁₈ R₁₉ together forms a heterocyclic group which is morpholyl,piperidyl, pyrrolidyl, or N-alkylpiperazyl;

--CR₁₇ NR₂₀ CO₂ R₂₁ where

R₁₇ is hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, and

R₂₀ and R₂₁ are the same or different and represent hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

--CR₁₇ C(OH)R₂₂ R₂₃ where

R₂₂ and R₂₃ are the same or different and represent straight or branchedchain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl, straight orbranched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms and

R₁₇ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms; ##STR26## where n is 0, 1, or 2,

R₂₄ is hydrogen, aryl, heteroaryl, straight or branched chain loweralkyl having 1-6 carbon atoms, or aryl or heteroaryl straight orbranched chain lower alkyl having 1-6 carbon atoms;

Z is methylene, oxygen, NR₂₅ or --CHCONR₂₅ where R₂₅ is hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,pyridyl, or phenylalkyl or pyridyl alkyl where each alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; and

T is methylene or oxygen.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. In some cases protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral the need for such protecting groups will be apparent to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE I ##STR27##

To a solution containing 3-Phenyl-imidazoline-2,4-dione (1.76 g) indimethylformamide (200 mL) at 0° C. was added 1M potassium tert-butoxide(10 mL) in tetrahydrofuran. After 5 min Copper (I) Iodide (1.9 gm) wasadded and the solution was allowed to stir at room temperature for 15min. 2-Chloro-3-nitropyridine (2.21 g) was then added and the mixturewas heated under nitrogen at 150° C. for 5 h. The mixture was cooled toroom temperature and then partitioned between saturated ammoniumchloride (250 mL) and ethyl acetate (200 mL) The organic layer waswashed successively with saturated ammonium chloride (2x), water (2x)and then dried with sodium sulfate. The solvent was removed at reducedpressure and purified by column chromatography to yield1-(3-Nitropyridyl)-3-phenyl-imidazoline-2,4(1H,3H)-dione as a whitesolid.

EXAMPLE II ##STR28##

To a solution of1-(3-Nitropyridyl)-3-phenyl-imidazoline-2,4,(1H,3H)-dione (500 mg) inmethylene chloride (20 mL) was added trisdimethylaminomethane (1 mL).The solution was allowed to sit at room temperature for 1 h followed byremoval of solvent at reduced pressure. The resulting red oil wasdissolved in acetic acid (25 mL) and added to a suspension of zinc dust(1.5 g) in acetic acid (50 mL). The mixture was heated to reflux for 5min and then cooled to room temperature over a 45 min period. Thereaction was filtered through celite and the acetic acid was removed atreduced pressure. Water (25 mL) was added and the resulting yellow solidwas collected and washed with ethanol to yield2-Phenyl-imidazo[1,5,a]pyrido[3,2-e]pyrazine-1,3(2H,5H)-dione (Compound1), m.p. 350° C. (dec.)

EXAMPLE III

The following compounds were prepared essentially according to theprocedures set forth in Examples I-II.

a)2-(2-Fluorophenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 2).

b) 2-(2-Fluorophenyl-4-ethoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione (Compound 3).

c)2-(4-Methylphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 4).

d)2-(4-Methoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 5).

e)2-(4-Ethylphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 6).

f)2-(4-Ethylphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 7).

g)2-(4-Ethoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 8).

h)2-(3-Methoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 9).

i)2-(4-n-Propyloxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 10).

j)2-(3-Ethoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 11).

k)2-(4-Isopropoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 12).

l)2-(4-Chlorophenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 13).

m)2-(3-Chlorophenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 14).

n)2-(4-Hydroxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 15).

o)5-N-Methyl-2-(4-Ethoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 16).

p)2-(4-Propylphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 17).

q)7-Methyl-2-(3-methoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 18).

r)7-Methyl-2-phenyl-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 19).

s)8-Chloro-2-(3-methoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 20).

EXAMPLE IV ##STR29##

To a solution of Ethyl 2-isocyanato-3-(dimethylamino)-propenoate (5.52g) in toluene (250 mL) was added aniline (2.79 g). The reaction wasstirred at room temperature for 30 min. The resulting solid wascollected and dried to yieldN-(1-Carboethoxy-2-dimethylaminovinyl)-N'-phenyl urea as a white solid.

EXAMPLE V ##STR30##

To a solution of Ethyl-2-N-3-(dimethylamino)-2-propenoate-N'-phenyl urea(2.31 g) in dimethylformamide (50 mL) was added triethylamine (0.1 mL).The solution was heated to 80° C. for 1 h cooled to room temperature andthen partitioned between water (200 mL) and Ethyl Acetate (200 mL). Theorganic phase was dried over sodium sulfate and the solvent was removedat reduced pressure to yield a reddish oil. Purification by columnchromatography yielded3-Phenyl-5-(dimethylaminomethylene)-imidazoline-2,4-dione as an offwhite solid.

EXAMPLE VI ##STR31##

To a solution of3-Phenyl-5-(dimethylaminomethylene)-imidazoline-2,4-dione (1.3 g) indimethylformamide (20 mL) at 0° C. was added 1M potassium tert-butoxide(5 mL) in tetrahydrofuran. After 5 min 2-Chlorocycloxeanone (700 mg) wasadded and the mixture was stirred for 30 min. Acetic acid (1 mL) wasadded and the solvent was removed at reduced pressure. To the resultingresidue was added ammonium acetate (10 gm) and acetic acid (25 ml) andthe mixture was heated to reflux for 4 h. The solvent was removed atreduced pressure and water (50 mL) was added. The resulting solid wascollected, washed with methanol and dried to yield2-Phenyl-6,7,8,9-tetrahydroimidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 21) as an off white solid, m.p. 236°-240° C.

EXAMPLE VII

The following compounds were prepared essentially according to theprocedures described in Examples IV-VI.

a)2-(4-Methylphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 22).

b)2-(4-Ethylphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 23).

c)2-(4-Chlorophenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 24).

d)2-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 25).

e)2-(2-Fluorophenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 26).

f)2-(4-Ethoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 27).

g)2-(3-Methoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 28).

h)2-(3-Ethoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 29).

i)2-(3-Chlorophenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 30).

j)2-(4-n-Propyloxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 31).

k)2-(4-Propylphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 32).

l)2-(4-Isopropoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 33).

m)5-N-Methyl-2-phenyl-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 34).

n)5-N-Methyl-2-(4-ethoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound (35).

o)2-(2-Fluoro-4-ethoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 36).

p)2-(2-Fluoro-4-methylphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 37).

EXAMPLE VIII

The following compounds were also prepared essentially according to theprocedures set forth in Examples I-VI.

a) 2-Phenyl-imidazo[1,5,a]pyrido[4,3-e]pyrazine-2,3(2H,5H)-dione(Compound 38).

b)2-(4-Ethoxyphenyl)-imidazo[1,5,a]pyrido[4,3-e]pyrazine-2,3(2H,5H)-dione(Compound 39).

c)2-(4-Ethoxyphenyl)-imidazo[1,5,a]thieno[3,2-e]pyrazine-2,3(2H,5H)-dione(Compound 40).

d)2-(4-Ethoxyphenyl)-imidazo[1,5,a]thieno[2,3-e]pyrazine-2,3(2H,5H)-dione(Compound 41).

e)2-(4-Ethoxyphenyl)-imidazo[1,5,a]thieno[3,4-e]pyrazine-2,3(2H,5H)-dione(Compound 42).

f)2-(4-Ethoxyphenyl)-cyclopent(e)-imidazo[1,5,a]pyrazine-2,3(2H,5H)-dione(Compound 43).

g)2-(4-Ethoxyphenyl)-cyclohept(e)-imidazo[1,5,a]pyrazine-2,3(2H,5H)-dione(Compound 44).

h)8-Benzyl-2-(4-methoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]pyrido[4,3-e]pyrazine-2,3(2H,5H)-dione(Compound 45).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR32## and thepharmaceutically acceptable non-toxic salts thereof wherein: X ishydrogen or lower alkyl having 1-6 carbon atoms;W isphenyl, thienyl, orpyridyl; phenyl, thienyl, or pyridyl, each of which is mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, amino, mono or dialkylamino where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms;##STR33## wherein: A represents nitrogen or C--R₁ ; B representsnitrogen or C--R₂ with the proviso that not both A and B are nitrogenand not both A and B are carbon; R₁ and R₄ are the same or different andrepresent hydrogen, halogen, straight or branched chain lower alkylhaving 1-6 carbon atoms, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms; R₂ ishydrogen, halogen, amino, 1-indanyl,4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl,4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), each of which ismonosubstituted with halogen, straight or branched chain lower alkylhaving 1-6, carbon atoms, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms; OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅, where R₅ ishydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; --CONR₆R₇ or --(CH₂)_(n) NR₆ R₇ wheren is 0, 1, or 2; R₆ is hydrogen, straightor branched chain lower alkyl having 1-6 carbon atoms; and R₇ ishydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; or NR₆R₇ forms a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl,or N-alkyl piperazyl; or C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same ordifferent and represent straight or branched chain lower alkyl having1-6 carbon atoms, phenyl, or phenylalkyl where each alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; and R₃ and R₅ arethe same or different and represent hydrogen or straight or branchedchain lower alkyl having 1-6 carbon atoms; or ##STR34## where n is 1;R₁₂ and R₁₃ are the same or different and represent hydrogen or straightchain or branched lower alkyl having 1-6 carbon atoms; and Y isN--R₁₄where R₁₄ ishydrogen, phenyl, pyridyl, straight or branched chain loweralkyl having 1-6 carbon atoms, phenylalkyl or pyridylalkyl where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;aminoalkyl where the alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkylis a straight or branched chain lower alkyl having 1-6 carbon atoms;1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl);1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl) eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; --COR₁₅ or --SO₂ R₁₅ where R₁₅ isstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,pyridyl, phenylalkyl or pyridylalkyl where each alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms, or phenylalkoxy orpyridylalkoxy where each alkoxy is straight or branched chain loweralkoxy having 1-6 carbon atoms.
 2. A compound of the formula ##STR35##wherein: W isphenyl, thienyl, or pyridyl; phenyl, thienyl, or pyridyl,each of which is mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, amino, mono ordialkylamino where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms; R₄ is hydrogen, halogen, straight or branchedchain lower alkyl having 1-6 carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms; R₂ ishydrogen, halogen, amino,1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl);1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl), eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6, carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms; OR₅, COR₅, CO₂ R₅, OCOR₅, or R₅,where R₅ is hydrogen, phenyl, pyridyl, straight or branched chain loweralkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;or --CONR₆ R₇ or --(CH₂)_(n) NR₆ R₇ wheren is 0, 1, or 2; R₆ ishydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms; and R₇ is hydrogen, phenyl, pyridyl, straight or branched chainlower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkylwhere each alkyl is straight or branched chain lower alkyl having 1-6carbon atoms; or NR₆ R₇ forms a heterocyclic group which is morpholyl,piperidyl, pyrrolidyl, or N-alkyl piperazyl; and R₃ and X are the sameor different and represent hydrogen or straight or branched chain loweralkyl having 1-6 carbon atoms.
 3. A compound of the formula ##STR36##wherein: W isphenyl, thienyl, or pyridyl; phenyl, thienyl, or pyridyl,each of which is mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, amino, mono ordialkylamino where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms; R₁ and R₄ are the same or different andrepresent hydrogen, halogen, straight or branched chain lower alkylhaving 1-6 carbon atoms, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms; and R₃ and X are the same or different andrepresent hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms.
 4. A compound according to claim 1, which is5-N-Methyl-2-(4-Ethoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.5. A compound according to claim 1, which is2-(4-Propylphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.6. A compound according to claim 1, which is7-Methyl-2-(3-methoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.7. A compound according to claim 1, which is7-Methyl-2-phenyl-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.8. A compound according to claim 1, which is: ##STR37## where R₁₂ andR₁₃ are the same or different and represent hydrogen or straight orbranched chain lower alkyl having 1-6 carbon atoms;W isphenyl, thienyl,or pyridyl; phenyl, thienyl, or pyridyl, each of which is mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, amino, mono or dialkylamino where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; R₁₄ishydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms;aminoalkyl where the alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkylis a straight or branched chain lower alkyl having 1-6 carbon atoms;1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydronaphthyl);1-indanyl, 4-(thia)deoxachromanyl, 1-(1,2,3,4-tetrahydro-naphthyl) eachof which is monosubstituted with halogen, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; --COR₁₅ or --SO₂ R₁₅ where R₁₅ isstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,pyridyl, phenylalkyl or pyridylalkyl where each alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms, or phenylalkoxy orpyridylalkoxy where each alkoxy is straight or branched chain loweralkoxy having 1-6 carbon atoms; and X represents hydrogen or straight orbranched chain lower alkyl having 1-6 carbon atoms.
 9. A compoundaccording to claim 1, which is8-Chloro-2-(3-methoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.10. A compound according to claim 1, which is2-Phenylimidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.
 11. Acompound according to claim 1, which is2-(2-Fluorophenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.12. A compound according to claim 1, which is2-(2-Fluorophenyl-4-ethoxyphenyl)-imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.13. A compound according to claim 1, which is2-(4-Methylphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.14. A compound according to claim 1, which is2-(4-Methoxyphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.15. A compound according to claim 1, which is2-(4-Ethylphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H )-dione.16. A compound according to claim 1, which is2-(4-Ethylphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.17. A compound according to claim 1, which is2-(4-Ethoxyphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.18. A compound according to claim 1, which is2-(3-Methoxyphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.19. A compound according to claim 1, which is2-(4-n-Propyloxyphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.20. A compound according to claim 1, which is2-(3-Ethoxyphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.21. A compound according to claim 1, which is2-(4-Isopropoxyphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5)-dione.22. A compound according to claim 1, which is2-(4-Chlorophenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.23. A compound according to claim 1, which is2-(3-Chlorophenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.24. A compound according to claim 1, which is2-(4-Hydroxyphenyl)imidazo[1,5,a]pyrido[3,2-e]pyrazine-2,3(2H,5H)-dione.25. A compound according to claim 1, which is2-Phenylimidazo[1,5,a]pyrido[4,3-e]pyrazine-2,3(2H,5H)-dione.
 26. Acompound according to claim 1, which is2-(4-Ethoxyphenyl)imidazo[1,5,a]pyrido[4,3-e]pyrazine-2,3(2H,5H)-dione.27. A compound according to claim 1, which is8-Benzyl-2-(4-methoxyphenyl)-6,7,8,9-tetrahydro-imidazo[1,5,a]pyrido[4,3-e]pyrazine-2,3(2H,5H)-dione.